In order to characterize the thermodynamics of the assembly of large macromolecular structures, we have carried out a differential scanning calorimetric study of the multiple conformational states involved in the assembly and maturation of the icosohedral head shell capsid of bacteriophage HK97. Using mutants of the gp5 head protein, we have been able to determine the energetic contributions of various structural features to the overall stability of the capsid shell. In general, for the twelve cases studied, the thermal and thermodynamic stability increases along the maturation pathway as the icosohedral capsid structure is perfected. The most outstanding result we have obtained is that the formation of covalent peptide cross-links between subunits resulting in intertwined catenated polypeptide chains produces a dramatic stabilization of the HK97 capsid structure and that the expansion transformation preceding cross-linking is energetically insignificant. This result is in marked contrast to the behavior of phages T4, T7, P22 and lambda, for which the major stabilization event is the expansion transformation. In HK97, the expansion transformation serves to facilitate the cross-link formation that greatly stabilizes the mature virus capsid (with A. C. Steven & R. L. Duda) The yeast prion protein, URE2P and its C-terminal portion (65 - 354), both in soluble and filamentous forms, all have the same thermal stability near 75degC. The difference in the enthalpy of denaturation of the complete 354 amino acid residue URE2P and the C-terminal (65 - 354) portion is approximately the energetic equivalent of two hydrogen bonds which indicates that there is only a very slight interaction of the N-terminal portion with the organized C-terminal domain. The Asp and Glu rich N- terminal domain, residues (1- 90), exhibits no cooperative melting behavior indicating that it is a disordered polypeptide chain until it is involved in amyloid formation. ( with A. Baxa & A. C. Steven) Complex formation between the transcription activator proteins TnSA and TnSC results in a 20degC increase in thermal stability. This is among the largest ever observed for protein-protein associations and is indicative of very tight binding. Thermal denaturation of the TnSA /TnSC complex is accompanied by a large positive heat capacity change that is consonant with the disruption of van der Waals interactions and the exposure to aqueous solvent of a large hydrophobic surface that is buried in the complex. These results provide thermodynamic support to the picture of the TnSA /TnSC complex obtained from the x-ray structural study that stimulated this investigation. Additionally, we have found that TnSA at physiological temperatures is partially unfolded unless complexed with TnSC. This finding calls into question certain protease assay results and their implied biological significance. ( with D.R. Ronning & F. Dyda)